Astellas Ireland Company Ltd.

(Kerry Plant)
Ampoule Inspection Machine

Eoin O’Sullivan
5th June 2014
Facility History
 Location

AICL-Dublin
Plant

AICL-Kerry
Plant
 Establishment September 1990
Established September 1990
AICL-Kerry Plant Official
Official Opening August
Opening August 1992
1992
Total Site Area 145,900 sqm.
TotalTotal
FloorSite Area 14,423
Space 146,400
sqm. sq.m.
Employees 294
 ASTELLAS IRELAND CO., LTD

• April 1, 2005: Astellas Pharma Inc. was established

following the merger of the former Fujisawa
Pharmaceutical Co., Ltd and the former Yamanouchi
Pharmaceutical Co., Ltd.

• October 1, 2005: Establishment of Astellas Ireland Co.,

Ltd (AICL) comprising of
• Astellas Ireland Kerry Plant
• Astellas Ireland Dublin Plant (API)
• Corporate Affairs, Dublin (Finance, IT, HR and ILB)
 Ampoule Filling Lines

OLD NEW
 Ampoule Visual Inspection

OLD NEW
Overview of Activities
 Summary of Processing and Packaging Lines
Processing/Packaging Line Product(s) Processed/Packaged

Ampoule Production Component preparation, Aseptic

Component Preparation and Filling Filtration & Filling, Inspection and
Packaging of Prograf Ampoules
Two Capsule Blending Lines Formulation and Filling of Prograf and
Three Filling Lines Advagraf Capsules

Two Blister Packaging Lines Packaging of Prograf and Advagraf

Capsules
One Ointment Packaging Line Secondary Packaging of Protopic Tubes

One Vial Packaging Line Secondary Packaging of Mycamine Vials

 Prograf Ampoules

Sterile Prograf solution is

aseptically filled and sealed
into sterilised glass ampoules. Each ampoule is visually
inspected.

Each ampoule is labelled

Packaged ampoules are
and packaged.
sold worldwide
Validation Approach
 Justification for the introduction of the AIM

Item PRG 5mg PRG 2mg

8 days 43 days
Total Manual VI time per batch
Approx. 2 weeks Approx. 9 weeks

Total AIM VI time per batch 1 Day 2 Days

 System description

• The AIM - “Ampoule

Inspection Machine” is
used in AICL for
visual inspection of
Prograf ampoules

• Machine throughput is
150 Ampoules per
minute
 Collection of Sample Rejects

• Prior to implementing the project, live sample rejects from manual visual
inspection were collected over a two year period.

• Samples were categorised into sample type, size and category.

• Identification of sample rejects was complete using a letter and numbering

sequence while maintaining a full record on a data system.

• Sample rejects were identified by applying their unique letter and number to
the tip of the ampoule using a thin black marker or by means of U.V. pen.
 Theory of Operation

• The AIM has 22 separate cameras - each designed to detect specific types
of defects

• Particles
• Colour ring
• Scratches / cracks
• Tip defects
• Blue Dye
• Fill Volume

• Colour ring, scratches, cracks, tip, fill volume and blue dye defects are all
detected by absolute methods – i.e. measurement against set points

• Particles are detected by dynamic comparison under both transmission and

reflected light.
 Oscillating drive

• The oscillating drive allows camera to move with ampoule when taking
pictures

– Patented technology by Eisai

– Allows taking pictures in static mode – no differential speed between the

ampoule and the camera

– Maximises inspection time without throughput impact

– No stop / start action required with the machine for inspection – smooth ampoule
flow path
 Pre - Spin

• The purpose of the pre-spin was an Astellas

driven requirement to
1. Eliminate the Schlering effect (shown in the
picture)
2. Eliminate any bubbles in the solution pre-
inspection – presence of bubbles would lead to
false rejects
 Particle Inspection Methodology
• The particle inspection methodology is based on the principle of

1) Spinning the container and liquid

2) Stopping the container suddenly
3) Taking a sequence of pictures while the liquid inside the container is still
spinning.
4) Comparing each picture in this sequence of pictures - a difference will show up
between pictures if there is a moving defect present in the liquid.

See explanation videos below

 Inspection Criteria

• Detection probability
– Characterisation of the particle detection process was driven by trying to
maximise detection probability.

– For particles this drove the design of the system with multiple cameras to
increase detection probability.

• False Reject Rate

– A key focus in the AIM development was to minimise the false reject rate in order
to eliminate unnecessary yield loss

• Improvement on Manual VI performance

– The AIM underwent a Knapp test as part of the validation process to prove it’s
superior detection performance to Manual VI.
 Overall detection – Manual VI vs. AIM

• A Knapp test was completed to compare Manual VI performance vs. AIM

performance.

• The efficiency value obtained from manual inspection is considered the

comparison parameter. The automated system must at least replicate this
value if not improve upon it, if it is to be considered a superior form of
inspection.

• As the ratio of FQA (manual visual inspection) verses FQB (Automatic

inspection) was 102.9%, AIM performance was proven to be greater than
manual visual inspection
 Strategy for balancing reject rate vs. detection capability

• The ideal solution would be 100% detection of all defects with no false
rejects thereby minimising the reject rate.
• However no vision process (manual or automatic) can give 100% detection
performance.
• Therefore in the interest of quality and safety we erred on the side of higher
defect detection performance and compromised with increased reject rate.

Ideal Balance

Reject Rate
Detection
Performance
 Reject Rate vs. FRR

This data was based on a small

5mg sample set and captured in a non
production environment.
FAT FRR 4.5%
2nd FAT FRR 0.3%
SAT FRR 0.5%

• Since the FAT / SAT the AIM sensitivity has been adjusted to minimise FRR.
• However getting real data on the FRR is difficult because
– 1) The AIM can see more defects than a human – so classifying what is real
and what is not is difficult.
– 2) The FRR has a random element to it – e.g. dust caused by environmental
conditions – the AIM sees the dust and captures this image but when checking
the ampoule later the dust is gone.
– 3) Some FRR is possibly still caused by variation in ampoule shape (e.g. base)
Most this has been tuned out now
Visual Inspection Approach
AIM Layout
 Functional & Challenge Testing

• Upon completion of machine reassembly after cleaning, a functional test is

performed to ensure machine is mechanically put together correctly.

• After the functional test, a Challenge test is run through the machine ensure
all cameras are functioning correctly.

• The Challenge test is made up of at least one type of each of the critical
rejects the AIM is capable of detecting. These rejects are from commercial
batches.

• The AIM must reject all ampoules in the challenge set before proceeding to
inspection of the batch.
 Visual inspection of a batch

• Ampoules are loaded onto infeed belt and pass through all inspection
stations of the AIM.

• Accept ampoules are discharged into one of two accept trays.

• Reject particle ampoules are discharged to reject tray no. 1, reject cosmetic
/ tip ampoules are discharged into tray no. 2

• Forced rejects (if the machine is powered down during the inspection or if
an alarm occurs) are discharged into tray no. 3 for re-inspection on
completion of the main batch
 AQL
• An AQL is from every batch processed through the AIM is manually visually
inspected.
 Critical is any particle >200 μm & any fibre > 2000 μm,Tips, height, blue
dye, chip, liquid volume & cross contamination
 Major is any particle <200 μm & any fibre < 2000 μm
Manually inspect
315 ampoules as
per FAP016

1 Critical / > 1 Major Defect i 8 Critical/Major 1 Major Defect

Investigate / take Sample a further

further action 315 ampoules

Are there
defects?

1 defect

0 defects

Pass Investigate / Take

further action
Specific Challenges
 Specific Challenges for AIM

Challenge Solution

Product Viscosity - Schlering effect & bubbles Pre-spin table

Product temperature requirements LED lighting – low heat

Not having a clear requirement of what the AIM List of defects put together & some ampoules
needed to reject & no measurement of particle sent off site for sizing.
sizes

Difficulty in detecting all defects types - cracks, Combination of backlight and reflective light as
particles, shape, colour well as colour and greyscale camera systems

Two fill volumes – 2mg & 5mg Upper and lower camera sets with minimum
changeover required

Transition from Manual VI to automatic Knapp testing to prove the increased

performance of the AIM
False Reject Rate Sensitivity, designed blind spots,
Environment.
Blind spots Minimise un-inspected areas.
Lower sensitivity inspection windows in close
proximity to blind spots – to maximise the
overall inspection area
 AIM Limitations

• The known limitation of the AIM, from a particle detection perspective, is

that it is designed to detect defects in the product solution.

• If a defect falls out of solution (e.g. sticks to the upper wall of the ampoule)
then there is a likelihood of no detection.

• A risk assessment was completed to focus on preventing possible defects

falling out of solution and preventative actions have been implemented to
mitigate against the risk, however it cannot be 100% guaranteed that all
particles will remain in solution.
 Changes made since the introduction of the AIM
• High tip reject rate – recipe developed further to allow acceptance of
correctly shaped tips.

• Incoming ampoules had a raised base causing false rejects, changes made
to window on base camera to accept these ampoules.
• False rejects were occurring during 2mg ampoule visual inspection due to a
reflection on the meniscus of the liquid - The two upper inspection window
positions were changed to “tilt” them in order to follow the meniscus slope.

As “Prevention is better than Cure” ongoing improvements are being

completed at the filling stage to prevent generation of unacceptable
ampoules.
 The Regulators
Two issues have been highlighted during regulatory inspections since the
introduction of the AIM in 2010.

• No expiry on the ampoules contained within the Challenge Set.

- Where possible an explanation was given as to why an expiry was not

required, i.e.: tip reject, studies were performed to assess the expiry for
other categories i.e.: blue dye ampoules from integrity testing & for the
remaining ampoules they are manually visually inspected every quarter by
trained & assessed operators ensuring that the defect may still be seen

• No visibility as to the correct version number in use for a particular

recipe.

• - A document was created detailing the breakdown of each recipe and its
corresponding current version number. There is a requirement in the MBR
to check the recipe on the AIM screen versus the document ensuring both
recipes match.
THANK YOU